Patients with melanoma who reported eating more fiber-rich foods when they began treatment with immunotherapy survived longer without cancer growth than patients with insufficient dietary fiber intake, according to new research published by Spencer et al in Science. The benefit was most noticeable in patients who did not take commercially available probiotic supplements. Parallel preclinical studies supported the observational findings.
Jennifer Wargo, MD
“Research from our team and others has shown that gut microbes impact response to immunotherapy treatment, but the role of diet and probiotic supplements has not been well studied,” said co–senior author Jennifer Wargo, MD, Professor of Genomic Medicine and Surgical Oncology at The University of Texas MD Anderson Cancer Center. “Our study sheds light on the potential effects of a patient’s diet and supplement use when starting treatment with immune checkpoint blockade. These results provide further support for clinical trials to modulate the microbiome with the goal of improving cancer outcomes using dietary and other strategies.”
Improved Progression-Free Survival
Patients who reported eating more fruits, vegetables, legumes, and whole grains met the study threshold for sufficient fiber intake. The 37 patients with sufficient fiber intake had improved progression-free survival (median = not reached) compared to the 91 patients with insufficient fiber intake (median = 13 months). Every 5-gram increase of daily fiber intake was associated with a 30% lower risk of cancer progression or death.
When the patients were further grouped according to high- or low-fiber diet and commercially available probiotic supplement use, response to immunotherapy was seen in 18 of 22 patients (82%) who reported both sufficient fiber intake and no probiotic use compared to the response seen in 60 (59%) of 101 patients who either reported insufficient fiber intake or probiotic use.
Response was defined as complete or partial complete or partial tumor shrinkage or stable disease for at least 6 months. Probiotic use alone was not associated with a significant difference in progression-free survival or odds of response to immunotherapy.
“Dietary fiber is important for gut health, just as it is important for overall health, and the two things are very tightly intertwined,” said co–senior author Carrie Daniel-MacDougall, PhD, Associate Professor of Epidemiology at MD Anderson. “In this study, we saw that dietary fiber also may be important to cancer treatment, which brings us to a point where we can design interventional studies to answer the questions that patients really want answered: ‘Does what I eat now matter, and could it impact my treatment outcome?’ We’re united in working to find answers for our patients.”
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Differences in Gut Microbiota and Preclinical Models
The study began with analyzing the gut microbiome profiles of 438 patients with melanoma, 321 of whom had late-stage disease and were treated with systemic therapy and 293 of whom had an evaluable response to treatment over follow-up. Most of these patients (87%) received immune checkpoint blockade, most commonly PD-1 inhibitors. A total of 158 patients also completed a lifestyle survey of antibiotics and probiotics usage; of these, 128 completed a dietary questionnaire as they began immune checkpoint therapy.
The research team reinforced their prior findings, which showed a higher abundance of Ruminococcaceae and Faecalibacterium prausnitzii—well-known and potentially beneficial bacteria involved in the digestion of fiber or starch—in patients who responded to immunotherapy. In contrast to the previous findings, overall diversity of gut bacteria was not associated with response to immunotherapy, potentially due to the larger size of this patient cohort.
The researchers also tested higher- vs lower-fiber diets and probiotic use in several preclinical melanoma models to shed light on the potential mechanisms behind the observational findings from the patient cohorts. In multiple models, probiotic use was associated with impaired response to immune checkpoint blockade, larger tumors, lower gut microbiome diversity, and lower levels of cytotoxic T cells in the tumor microenvironment. A high-fiber diet was associated with slower tumor growth and significantly higher frequency of CD4-positive T cells in preclinical models treated with PD-1 inhibitors.
Clinical Trial to Build on Findings, Test Effect of Dietary Intervention
Based on the early study findings, a randomized clinical trial (ClinicalTrials.gov identifier: NCT04645680), led by co–first author Jennifer McQuade, MD, Assistant Professor of Melanoma Medical Oncology at MD Anderson, will examine how whole food–based diets with varying fiber content affect the microbiome and immune response. The study is currently enrolling patients with stage III to IV melanoma who are receiving immunotherapy.
Disclosure: The study was supported by the Melanoma Moon Shot®, part of MD Anderson’s Moon Shots Program®. Additional research support included funding from National Institutes of Health and National Cancer Institute, the Andrew Sabin Family Fellowship Program, Department of Defense, MD Anderson Multidisciplinary Research Program, MD Anderson Physician Scientist Program, Melanoma Research Alliance, Sean Parker Institute for Cancer Immunotherapy at MD Anderson, Stand Up to Cancer, and U.S.-Israel Binational Science Foundation. For full disclosures of the study authors, visit science.org.
